Welcome to Medical Inflammation Research at Karolinska Institutet!

Medical Inflammation Research at Karolinska Institute

Humanity is suffering from many inflammatory diseases affecting specific tissues of the body. In rheumatoid arthritis, the joints of hands and feet are inflamed and destroyed, in multiple sclerosis the spinal chord and brain, in diabetes insulin-producing cells of the pancreas, in lupus the kidneys and in Sjögren´s syndrome the salivary glands. In spite of very large research efforts we do not know why these diseases develop and we have no effective curative treatment for them.

At Medical Inflammation Research (MIR) we believe that it is necessary to take one step back to advance two steps forward. We need to analyse the basic mechanisms behind these diseases and for this work we need animal models. With the animal models we try to find out which genes are important for the human diseases and why the immune system suddenly starts to attack our own tissues. With the increased knowledge we hope to find new ways to predict the diseases, to develop new therapies to stop the disease process and optimally to find ways to completely abrogate development of disease in susceptible individuals.

Our main goals are:

1) To identify the genes that control animal models for rheumatoid arthritis and multiple sclerosis.

2) To use the animal models not only for understanding the basic mechanism of autoimmune disease but also as models for developing new diagnostic, preventive and therapeutic strategies.

3) To understand the role of MHC class II genes in explaining the immune specificity of autoimmune disease.

Read more about the work at Medical Inflammation Research (pdf).

 

Medical Inflammation Research (MIR) is a division within the department of Medical Biochemistry and Biophysics (MBB) at Karolinska Institutet (KI). It is located in the Scheele house (main lab with all animal model work) and the Center for Molecular Medicine (CMM) (with all clinical part of the research).

Postdoc in bioinformatics (MIR-1503) – International recruitment

A postdoc position in a project to develop a diagnostic biomarker assay for rheumatoid arthritis is now open.  It is placed at Southern Medical University, Guangzhou, China and the research will be performed at both SMU and at Karolinska Institutet, Stockholm, Sweden.

Form of employment:

Full-time, 3 years (with a trial employment for 6 months) and with a possibility of prolongation.

Start: as soon as possible.

Apply before: Nov 23, 2015.

Description:

Applications are invited for a position as a postdoc in a project led by Prof. Rikard Holmdahl. The task is to develop multiplex assays for detection of antibodies to defined protein epitopes and to analyse both experimental animal models and human samples.

Project:

The project aims to develop a diagnostic test for rheumatoid arthrtitis. The test is based on unique antigenic epitopes derived from various joint proteins. The epitopes has been formulate as conformational peptides but needs to be further improved regarding their functional and diagnostic role. As these peptides and epitopes are shared between mice and humans that are possibilities to make in depth functional analysis in the mouse as well as testing of human sera for assay development. The assay development will be developed using a multiplex platform, and also analyzed in detail regarding their physical properties. Thus solid-phase assays using ELISA will be compared with multiplex platforms using other technologies, one of them based on a Luminex platform. The project involve both in depth analyses and the coordination of large cohorts. This includes analyses with advanced statistical methods. Besides the laboratory work the position will also involve coordination of the project with participating clinicians in both China and Europe.  The goal is to develop a suitable diagnostic test and to publish the results in leading international journals.

Qualifications:

To qualify, the applicant must hold a PhD in medicine or biological science. Fluent English is an absolute requirement as the lab working language is English. Easiness with social communication are requirements. Computer skills, bioinformatics knowledge and statistical analysis are needed. Laboratory experience and excellence is a requirement.

Contact and Application:

Apply directly to Angel Yao Mattisson (Angel.Yao-Mattisson@ki.se). Please mention the job number (MIR-1503) in your application.

Postdoc in biochemistry (MIR-1502) – International recruitment

A postdoc position in a project to analyze the role of antibodies and joint proteins in rheumatoid arthritis is now open.  It is placed at Southern Medical University, Guangzhou, China and the research will be performed at both SMU and at Karolinska Institutet, Stockholm, Sweden.

Form of employment:

Full-time, 3 years (with a trial employment for 6 months) and with a possibility of prolongation.

Start: as soon as possible.

Apply before: Nov 23, 2015.

Description:

Applications are invited for a position as a postdoc in a project led by Prof. Rikard Holmdahl. The task is to identify, produce and analyse proteins of critical importance for development of rheumatoid arthritis.

Project:

The project aim to basic mechanisms of importance in the development of  rheumatoid arthrititis. The test is based on already unique antigenic epitopes derived from various joint proteins and antibodies derived from rheumatoid arthritis patients. The epitopes has been formulate as conformational peptides but needs to be further improved regarding their functional and diagnostic role. As these peptides and epitopes are shared between mice and humans there are possibilities to make in depth functional analysis in the mouse as well as testing of human sera for assay development. The project involves establishment of human monoclonal antibodies and purification of polyclonal antibodies from RA patients. These will be analysed in vitro as well as in mouse models. The identification of new epitopes will require both in depth and large scale biochemistry including HPLC, mass-spectrometrometry and a range of analytical methods. Development and production of recombinant proteins using different expression system The ultimate goal is to contribute to the development of new diagnostic tests and vaccination to prevent the development of rheumatoid arthritis. Results are expected to be published in leading international journals.

Qualifications:

To qualify, the applicant must hold a PhD in medicine or biological science. Fluent English is an absolute requirement as the lab working language is English. Excellence in protein biochemistry is a requirement. Computer skills, bioinformatic knowledge and experience in cellular immunology are needed.

 

Contact and Application:

Apply directly to Angel Yao Mattisson (Angel.Yao-Mattisson@ki.se). Please mention the job number (MIR-1502) in your application.

Postdoc in experimental immunology (MIR-1501) – International recruitment

A postdoc position in a project to investigate basic mechanisms and development of a vaccine for rheumatoid arthritis is now open.  It is placed at Southern Medical University and the research will be performed at both SMU and at Karolinska Institutet Sweden.

Form of employment:

Full-time, 3 years (with a trial employment for 6 months) with a possibility for prolongation.

Start: as soon as possible.

Apply before: Nov 23, 2015.

Description:

Applications are invited for a position as a postdoc in a project led by Prof. Rikard Holmdahl. The task is to develop multiplex assays for detection of antibodies to defined protein epitopes and to analyze both experimental animal models and human samples.

Project:

The project aims to develop a vaccine against rheumatoid arthritis. The vaccine is based on unique antigenic epitopes derived from specific joint proteins. The project is designed to investigate the basic mechanism of B and T cell tolerance of importance for the vaccination effect. This work is done primarily in mouse models in which epitopes and interacting molecules have been genetically modified. As the epitopes in the vaccine it is shared between mice and humans that are possibilities to make in depth functional analysis also with human samples. The main work will be done with experimental animals and an excellent platform for the work will be available. The goal is to contribute in the development of vaccine against rheumatoid arthritis and to publish the results findings related to basic mechanisms in autoimmunity and vaccination results in leading international journals.

Qualifications:

To qualify, the applicant must hold a PhD in medicine or biological science. Fluent English is an absolute requirement as the lab working language is English. Training and excellence in experimental immunology and with experimental mouse systems is a requirement. Computer skills, bioinformatics and statistical knowledge are needed.

Contact and Application:

Apply directly to Angel Yao Mattisson (Angel.Yao-Mattisson@ki.se). Please mention the job number (MIR-1501) in your application.

Vacant Positions

Current Vacant Positions
(updated 24th September 2015)

Postdoc in experimental immunology (MIR-1501) – International recruitment

Postdoc in biochemistry (MIR-1502) – International recruitment

Postdoc in bioinformatics (MIR-1503) – International recruitment

 

Previously announced and completed positions

MIR Publications

2011			2012			2013			2014			2015			2016
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2016

1. Brink M, Hansson M, Mathsson-Alm L, Wijayatunga P, Verheul MK, Trouw LA, Holmdahl R, Rönnelid J, Klareskog L, Rantapää-Dahlqvist S. Rheumatoid factor isotypes in relation to antibodies against citrullinated peptides and carbamylated proteins before the onset of rheumatoid arthritis. Arthritis Res Ther. 2016 Feb 9;18(1):43.
2. Holmdahl R, Sareila O, Olsson LM, Bäckdahl L, Wing K. Ncf1 polymorphism reveals oxidative regulation of autoimmune chronic inflammation. Immunol Rev. 2016 Jan;269(1):228-47. doi: 10.1111/imr.12378. Review.
3. Shakya AK, Kumar A, Holmdahl R, Nandakumar KS. Macrophage derived reactive oxygen species protects against autoimmune priming with a defined polymeric adjuvant. Immunology. 2016, 147:125-32.

JOINT ID

Joint ID is a scientific project funded by SSF with an aim to develop a new diagnostic test for RA patients.

Collaborators:

• Rikard Holmdahl, Karolinska Institute, Stockholm (Co-ordinator)
• Jan Khilberg, Uppsala University, Uppsala
• Inger Gjetsson, Gotenborg University, Gotenborg

Rikard Holmdahl CV

CV (10 Aug 2015)

Rikard Holmdahl 530328

1) Division of Medical Inflammation Research, Department of

Medical Biochemistry and Biophysics (MBB), Karolinska Institutet, and Rheumatology Research Unit, Department of Medicine (CMM), Karolinska University Hospital, 171 77 Stockholm,

Sweden. Visitors address: Dept of Medical Biochemistry and Biophysics, Karolinska

Institutet, Scheeles väg 2, Solna, Sweden. email: Rikard.Holmdahl@ki.se, Phone: +46-852484607. web address: www.inflam.mbb.ki.se

2) Biocity/Medicity, Tykistökatu 6-A4, 20520 Turku, Finland. email: rikhol@utu.fi, Phone: +358-23337015

ORCID identifier: http://orcid.org/0000-0002-4969-2576

 

A. Professional preparation

1971-1976 industrial employments (Nymans/Uppsala/, Alfa Laval /Tumba/, Sandvik Coromant /Stockholm/).

1976-77 Biochemistry 1 year (Stockholm/Uppsala University),

1977-87 Medical education 5.5 years (Uppsala University),

1981-85 PhD education including paternal leave for 6+3 months

1985 (27 Sept)  PhD (Uppsala University)

1987 MD (Uppsala University)

1987Associate professor (docent) (Uppsala University)

1988-1989 Clinical residency training, University Hospital, Uppsala

1990-93 Research fellow, Medical Research Council in Sweden

 

B. Appointments

Professor in Medical Inflammation Research 1 Feb 1993-08 (Lund University)

Guest Professor at the Finnish Academy (50%) 2007-11 (University of Turku)

Professor in Medical Inflammation Research, 1 Jan 2008 (Karolinska Institutet)

Guest scientist University of Turku from 1 jan 2012

Guest professor at Southern Medical University Guangzhou, 2012-

 

C. Commision of trust

93- Head of the Medical Inflammation Research Laboratory

93-08 Animal house director (ansvarig djurföreståndare) Immmunobiology Lund

95-98 Member of the board for Dept of Cell and Molecular Biology

96- Member of the editorial board of Scandinavian Journal of Immunology

97- Member of the editorial board of European Journal of Immunology

98-01 Director of the Immunobiology house

98-01 Member of the advisory board of the medical faculty, Lund University

99-14 Associated editor for Arthritis Research

99- Member of the international advisory board of Modern Rheumatology

01-05 Member of the medical faculty board, Lund University

02-06 Member of the editorial board of Journal of Autoimmunity

02-  Member of the editorial board for the Journal of Experimental Animal Science

03- Member of the scientific evaluation commite for King Gustav the 80 year foundation in Sweden

03-09 Member of the scientific advisory board of the German Center for Rheumatology Research in Berlin

03-13 Member of the Executive Committee of European Journal of Immunology

04-12 Board member of Scandinavian Foundation for Immunology

04- Member of the editorial board for Current Rheumatology Reviews

04-06 Member of Faculty 1000 in Medicine

04-08 Director of the programme area “Chronic Inflammation Research programme” in Lund University

06-09 Guest professor at Xian Jiao Tong University

07-11 Guest professor Finnish Academy/University of Turku (50% employment)

07-17 Scientific advisor for the excellence center in Oslo “Center for immune regulation, CIR”

14-24 Scientific advisor for the excellence center in Oslo “Jebsen inflammation research centre”

12- Guest scientist at Turku Unviersity

12- Guest professor at Southern Medical University, China

14- Member of the Nobel Assembly

15- Member of the governmental advisory board for gene technology in Sweden

•  Referee/advisor for Nature, Nature Medicine, Nature Genetics, Nature Immunol, Science, PNAS, J Exp Med, FASEB J, Eur J Immunol, J Immunol, J Mol Med, Am J Hum Genetics, Hum Mol Gen, Arthritis Rheum, Arthritis Res&Therapy, J Clin Invest and other journals.

• Referee/advisor for Science Research Council in Sweden, Danish Research Council, Gustav Vs 80-årsfond, Wellcome Trust, ARC (Arthritis Research Council, UK), research councils in Finland, Netherlands, Germany, Austria, Israel and Hong Kong and other foundations.

D. Invitations

Invited as lecturer or chairman to more than 200 international meetings, some examples; plenary lectures at International immunology Congress, European Congress of immunology, German, British and Scandinavina Congresses of Immunology. European Congress of Rheumatology, Several Keystone, Cold Spring Harbor, Gordon meetings, International inflammation Congress etc  

2003: International Congress of Immunology, European Immunology congress, German Society for Immunology, British Society for Immunology, Scandinavian Society for Immunology, Keystone Symposia in Autoimmunity, Gordon Conference on Collagen, The American Society for Matrix biology, Cold Spring Harbor Symposia on Genomics, International Glycobiology meeting, Ectrims (European Multiple Sclerosis meeting), European Rheumatology meetings, European Science Foundation meetings, several Nobel symposia etc

Turku Medical Faculty, plenary lecture; Rostock Medical Faculty, Rostock, Germany, plenary lecture; European Federation for immunogenetics, Baden-Baden, Germany, plenary lecture; European Congress of Immunology, Rhodos plenary lecture; Scandinavian Congress of Immunology, Rejkjavik, plenary lecture; NIH MS Genetic Workshop, Washington DC; 8th International Workshop on Autoantibodies and Autoimmunity (IWAA), Berlin, plenary lecture; GARN Congress Japan, plenary lecture; Biotech Symposia, Stockholm, plenary lecture; Neuroscience genetic workshop, Tubingen, Germany, plenary lecture; Cold Spring Harbour Symposia on Genomics, plenary lecture

2004: Oxford Univeristy, invited speaker; Kennedy Institute of Rheumatology, invited speaker

; Institute of Child Health London, invited speaker; Hudding Hospital, Strategic center for infectious diseases, invited speaker; Akademiska Hospital, Rheumatology, invited speaker; Genetics and bioinformatics workshop, Rostock University, invited speaker; Danish Immunology Society, Panum institute Copenhagen, invited speaker; European Rheumatology Congress, Berlin, plenar lecturesx2; Scandinavian Congress in Rheumatology, Göteborg, invited speaker; EFIS Eurpean Federation of Immunological Societes meeting in Belgrad, invited speaker; Rat genome workshop, Copenhagen, organizer and chairman; GARN meeting, Montreal, invited speaker; International Neuroimmunology Congress, Venice, Italy, invited plenary lecture; International Congress of Immunology, Montreal, chairman and plenar lecture; EUROME meeting London, invited speaker

2005: Allergic diseases symposia, Malmö, Biotech Symposia Medicon Valley, Copenhagen, Chairman, European Congress in Rheumatology, Vienna, responsible for basic science program, invited speaker and chairman, FASEB Conference Vermont, USA, invited speaker , Berlin, Germany, Cellaid, workshop on cellular therapy meeting, invited speaker, Genetics of autoimmune disease, workshop Lofoten, Norway, invited speaker, Scandinavaian/German congress of Immunology, Kiel, invited plenary speaker and prize for honory lecture, Erlangen clinical research meeting, invited keynote speaker, Newcastle University, invited speaker, British Society for Immunology, invited plenary speaker

2006: Invited key note speaker at the Canadian sociatiy for connective tissue research, Ottawa, invited speaker Feinstein college of medicine, Long Island,

Key note speaker Nova Nordisk 060609, European Congress in Rheumatology, Amsterdam, responsible for basic science program (2006), Invited speaker at Xian University July 06, Basic Theory Institute in Bejing 06, Catholic University Seoul, South Korea 06, invited speaker and chairman MUGEN 1^st conference in Athens 06, Invited speaker Cellaid 2nd conference in Bryssel 06, Invited Rudbeck speaker Uppsala university 06, invited speaker workshop on citrullination in rheumatic diseases Kennedy institute, London, invited main speaker at Glycobiology conference Oulo, Finland, invited speaker German National Rheumatology meeting Wiesbaden 06, invited speaker European Science foundation Schering workshop Potsdam 06, invited speaker South Europe Clinical immunology Conference 06, invited speaker Oxford University diabetes program, Invited speaker EMBO course Kanpur, India.

2007:Invited speaker Turku University Jan, Invited speaker EURATOOL meeting Prag Feb, •Invited speaker MS Forum workshop, Wiesbaden 070224, Invited speaker first biomarker conference, Lillehammer 070412-14, International Inflammation Research Congress, Copenhagen, invited speaker, chairman and member of scientific commitee (2007), FASEB workshop in autoimmunity, Vermont USA, invited speaker, International Congress of immunology Rio, Brazil, chairman and speaker, Congress of animal science, plenary speaker, Tokyo, European Neuroimmunology Congress, Oxford (sept 07) invited speaker, Cold Spring Harbor workshop on rat genetics, chairman and speaker, New York,

2008:  Speaker, autocure, Potsdam 080129, speaker MUGEN Athens 080128, speaker euratool workshop Glasgow 080303, Invited speaker Finnish Connective Tissue workshop 080328, Invited plenary speaker Congress of Immunogentics Toulose 080303-5, Invited plenary speaker Gordon Confernce in Connective Tissue Biology, New Hampshire USA 080401-5, Invited plenary speaker Scandinavian Congress in Immunology Stockholm 080812-15, Gordon conference in autoimmunity Oxford 080917-21, Invited plenary speaker DAMP workshop Pittsburgh 080826-30, Invited plenary speaker Berzelius symposium Linköping 0804-6, Invited speaker, Reumaförbundet research info patient 081012, Invited speaker Geneva University 081029-30, Invited speaker Nueropromise Toulouse 081103-5, invited speaker Oxford University 081118, Invited plenary speaker Rat Genetic ColdSpringHarbor Rat genetics Cambridge 081203-6, Invited speaker Oslo University 081210-12, Invited speaker Bergen University 081218, Opponent + lecture Göteborg 081219.

2009: Invited speaker Lund University TIM workshop 090123, speaker Autocure Berlin 080126-27, Invited speaker Greifswald University 080202, Chairman dissertation Lund University 090213, Speaker Euratools Barcelona 090226-28, Invited plenary speaker Gordon conferance on Redox systems Pisa Italy 090309-11, Invited plenary speaker Cellaid workshop Potsdam 090318-19, Speaker Center for Genomics workshop Sandhamn 090422-24, Invited plenary speaker workshop Vienna genetic center 090512, Invited plenary speaker Gordon conference on Connective tissue Switzerland 090609-11, Speaker Masterswitch workshop Athens 090628-29. Invited speaker DNAX Los Angeles and UCLA, 090713-17, Chairman ws-speaker European Congress of Immunology Berlin 090913-15, Inivted plenary speaker German Congress of Rheumatolgoy 090925-26, Speaker MUGEN Athens 091006-10, Speaker Neuropromise Athens 091108-9, Chairman Dissertaiotn Lund University 091127, Invited speaker Madrid University 091127-30,

2010: Invited plenary speaker workshop autoimmune disease Coimbra Portugal 100105-7, Speaker autocure Berlin 100124-26, Invited speaker Workshop on biomarkers in arthritis Rome 100218-22, speaker workshop autoimmunity Zurich 100318-19, plenary speaker, congress in physiology Copenhagen 100327-30, Advisor Center for Immunology ws Geilo 100414-16, speaker Center for genomics ws Uppsala 100428-29, speaker IMI Leiden 100513-14, speaker euratrans Berlin 100527-28, speaker Masterswitch Madrid 100627-28, speaker Cartilage workshop KI Stockholm 100703-4, speaker ws Saltsjöbaden 100812-23, invited plenary speaker ws mouse vs human autoimmunity Oxford 100920-22, invited plenary speaker OARSI Bryssel 100924-26, invited speaker/guest prof Univ Lincoln Nebraska 101020-1105, invited speaker GARN meeting Zurich 101008-9, invited speaker Homburg University 101015, speaker IMI Leiden 101023-26, invited plenary speaker Antooxidant-redox workshop Cologne 101103-6, invited speaker Lubeck Univ 101202-4, invited speaker Diabetes ws New York 101211-14,

2011: chairman/speaker Guangzhou 110103-7, speaker neurinox Geneva 110121, speaker autocure Amsterdam 110124-25, chairman/speaker COLL meeting Sigtuna 110210-11, Keystone meeting Glycobiology Canada 110305-12, invited speaker autoimmunity workshop Helsinki 110414, invited plenary speaker British society for Immunology Aberdeen Scotland 110508-8, chairman project organizer Guangzhou 110529-31, Masterswitch Leiden 110619-21, invited speaker Fraunhofer Aachen 110826, speaker BTC Prag 110828-30, invited speaker Oslo Univeristy 110905-6, opponent Helsinki 111007, speaker B cell workshop Göteborg 111011-12, invited speaker ECTRIMS Amsterdam 111019-22.

2012: speaker Neurinox Geneva 120121-24, invited plenary speaker EWRR Stockholm 120223-4, Chairman animal model workshop BTC 100 participants Stockholm 120324-28, invited speaker CHIP ws Lund University 120330, chairman/speaker COLL ws 120410-12, speaker MBB workshop Nynäshamn 120514-15, speaker euratrans Munich 120604-6, Lecturer KI course in redox regulation 120610-15, speaker Masterswitch Athens 120617-19, plenary speaker Int MS workshop Stockholm 120830-31, invited plenary speaker Eur Congress of immunology 120906-9, speaker BTC Prag 120910-12, speaker B cell net meeting Sigtuna 121022-23, invited speaker Dusseldorf/Frankfurt/Aachen 121122-23, invited speaker ws Rat genetics Cambridge 121203-7,

2013: Chairman/speaker Guangzhou 13014-21, speaker Frankfurt Univ 130220-21, invited speaker Uppsala Univ 130308, invited speaker MIR historic retreat 130320-21, speaker Neurinox Zurich 130417-18, invited speaker NovoNordisk Copenhagen 130513, invited speaker Bergen University 130515, speaker BTC Athens 130605-7, speaker Redox KI retreat 130829-30, invited plenary speaker German Congress of Immunology Mainz 131012-14, speaker BTC Prag 131015-16, speaker MBB retreat Nynäshamn 131019-20, invited plenary speaker Macrophage regulation, Erlangen 131011-12, chairman Kiim workshop north sthlm 131017-18,  chairman/speaker Guangzhou 131101-7, chairman COLL 131202-3,

2014: speaker Frankfurt/Berlin 140324-25, invited speaker connective tissue cworkshop Cologne 140501-3, invited speaker Muenster University 140507, speaker Animal Model workshop Vienna140516-17, invited speaker workshop Center for Immunology research, Oslo 140819, speaker EU Neruinox workshop in Athens 140918, speaker Psoriasis arthritis workshop Frankfurt 141016

E. Organisation of meetings

Meeting president of an international course in experimental rheumaimmunology, 150 paticipants, Sätra Brunn Spa, Uppsala, Sweden 1988

Meeting president of Scandinavian Societies for Immunology 30^th meeting, 400 participants, Lund, Sweden, 1999.

Coorganizer of the Benzon foundation workshop on Multiple sclerosis, 100 participants, Copenhagen  2002

Member of the scientific commite for the International Congress in Immunology, 7000 participants, Stockholm 2001

Meeting president of the Fernström Jubileum symposia; Functional genomics of inflammation, 150 participants, Lund 03

Member of the scientific commite for the European Rheumatology Congress (EULAR) in Europe for 2004,2005 and 2006. 7-11000 participants

Member of the scientific commite for the MUGEN 1^st conference on “Animal models for human immune diseases” in Athens sept 2006, 150 particpants

Responsible organizer of the “Neuropromise course for genetic and bioinformatics analysis” in Lund with 30 participants from all over Europe during one week including both theoretical and practical training.

Member of the scientific commite for the International Congress in Inflammation research, 5000 participants, Copenhagen 2007

Coordinator and meeting president Baltic Summer School 4-21 Sept 07, 120 participants

Meeting president, EURATOOL workshop, 50 participants, 10 speakers, Stockholm Nov 08.

Meeting president, First workshop for standardisation or animal models for rheumatoid arthritis, March 2012.

Meeting president, OSTEOIMMUNE Training School and annual meeting, 40 participants, Nov 2013

 

F. Awards, honours etc

1988 The Benzelius prize, Royal Science Society, Uppsala

1989 The Craaford prize, Anna Greta Craaford foundation for rheumatology research.

1992 The Fernström prize, Eric Fernström foundation for medical research

1994 The Göran Gustafsson prize in medicine, Göran Gustafsson foundation, Royal Science Academy, Stockholm, Sweden

2002 The European Descartes prize (shared with Lars Fugger, Yvonne Jones and Colin Watts)

2003 The SalusAnsvar Nordic Medical prize (shared with Andrej Tarkowski)

2005 The European Federation of Immunological Societies, Lecture award, DfGI/SSI Kiel

2006 Research group Medical Inflammation Research selected as an Excellence center for rheumatology research by EULAR (the European Rheumatology Association)

2011 Selected with highest possible marks, “Outstanding” by the International evaluation of Karolinska Institutet 2011 (ERA).

 

G. Entrepreneurial achievements

00-08 Member of Scientific Advisory Board for Resistentia Pharmaceutical AB

00-06 Cofounder of Arexis AB and member of the board from the start

00-10 Member of the Scientific Advisory Board for Bankinvest Biotech, Copenhagen (one of the largest venture capital investor in biotech in Scandinavia).

02-07 Member of Scientific Advisory Board for Cartela AB

03-10 Scientific consultant for Oxypharma AB

06- Scientific consultant for Hansa Medical AB

08- Cofounder of Redoxis AB, Chairman of the board

09- Board member and from 2012 chairman in the board of Pronoxis AB

12- Cofounder and board of Curara AB

 

H. Educated PhD students and postdocs

Theses of graduate students examined under the main supervision

1) Mikael Andersson: 901214, "Self reactivity and tolerance in the immune system. Studies on T cells in murine type II collagen-induced arthritis",

Medical Faculty, Uppsala University, opponent Antonio Coutinho, Paris

Present position: Pharmaceutical assessor at the Division of Pharmaceutics and Biotechnology, Medical Products Agency(MPA), Uppsala, Sweden

2) Tom J Goldschmidt: 910927, “T lymphocytes in autoimmune arthritis. Monoclonal antibody treatments in mouse and rat”, Medical Faculty, Uppsala University, opponent Anne Cooke, Cambridge

Present position: Scientific advisor, SciLife, Stockholm

3) Liselotte Jansson, 940330; “Sex mediated influence in experimental models for rheumatoid arthritis and multiple sclerosis” Medical Faculty, Uppsala University, opponent Paul Wooley, Detroit

Present position: Research section leader Astrazeneca, Göteborg

4) John A Mo, 941007; “B cell recognition of type II collagen in mouse cartilage” Medical Faculty, Uppsala University opponent Dan Holmberg, Umeå

Present Position: Scientist, Astrazeneca, Göteborg, Sweden

5) Erik Michaëlsson, 960404, “T cell recognition of type II collagen – A cartilage glycoprotein of importance for autoimmune arthritis”, Medical Faculty, Lund University, opponent Polly Matzinger, New York

Present position: Research team leader, Astrazeneca, Göteborg, Sweden

6) Vivianne Malmström, 970920, “Arthritis susceptibility and tolerance in collagen transgenic mice”, Medical Faculty, Lund University, opponent Erna Möller, Stockholm

Present Position: Associate professor, Karolinska Institutet, Stockholm, Sweden

7) Carina Vingsbo-Lundberg, 971108, “Chronic autoimmune arthritis in rats; pathogenesis and genetic factors”, Medical Faculty, Lund University, opponent Frank Emmrich, Leipzig

Present position: Scientist and section director, Statens Seruminstitut, Copenhagen

8) Ulrica Brunsberg, 980516,”The importance of major histocompatibility complex class II genes for the development of autoimmune inflammation”, Medical Faculty, Lund University, opponent Ulf Gyllensten, Uppsala

Present position: Pharmaceutical assessor at the Division of Pharmaceutics and Biotechnology, Medical Products Agency(MPA), Uppsala, Sweden

9) Peter Kjellén, 991201,” The structural basis of MHC control in experimental autoimmunity”, Medical Faculty, Lund University, opponent Sören Buus, Copenhagen

Present Position: Ass prof, Örebro University

10) Alexandre Corthay, 000310, “T cells in autoimmunity, studies on murine type II collagen induced arthritis”, Medical faculty, Lund University, opponent George Kollias, Athen

Present position: Associated prof, Dept of Immunology, Oslo University, Norway

11) Johan Jirholt, 001215, “A search for genes influencing autoimmunity. Focus on rheumatoid arthritis and multiple sclerosis”, Medical faculty, Lund University, opponent Holger Luthman,  Stockholm

Present position: Scientist, Astrazeneca, Göteborg

12) Mikael Vestberg, 010126, “MHC and transgenic mice. A study into function and polymorphism of class I and class II molecules”, Medical faculty, Lund University, opponent Jan Böhme, Stockholm

Present position: Head of Transgenic Unit, Oslo University

13) Ann-Sofie Hansson, 011019, “New models for relapsing polychondritis and rheumatoid arthritis, focus on the tissue specifc response”, Medical faculty, Lund University, opponent Norman Staines, London

Present position: Scientist/Clinician, Clinical Immunology, Lund University

14) Åsa Johansson, 011019, “T cells, cytokines, and genetic factors in autoimmunity. Studies of experimental models of arthritis and sialadenitis”, Medical faculty, Lund University, opponent Linda Wicker, Cambridge

Present position: Scientist/Clinician, Hematology, Lund University, Lund

15) Shemin Lu, 020212, “Genetic  analyses and vaccination  of rat models of arthritis”, Medical faculty, Lund University, opponent Raimund Kinne, Jena

Present position: Professor and head of Dept of Immunology, Xian University, China

16) Lars Svensson, 020213, “Role of B cells and cytokines in arthritis”, Medical faculty, Lund University, opponent Hans Carlsten, Göteborg

Present position: Scientist, section head, LEO Pharma, Copenhagen

17) Johan Bäcklund, 020924, “Studies on T cells reactive with posttranslational modifcation in arthritis”, Medical faculty, Lund University, opponent Ludvig Sollid, Oslo

Present position: Associate professor, Karolinska Institutet

18) Patrik Wernhoff, 020924, “Genetic control of autoantibodies in experimental autoimmune disease”, Medical faculty, Lund University, opponent Claudia Berek, Berlin

Present position: Scientist, Lund University

19) Peter Olofsson, 030527, “Identification of arthritis regulating genes in rats”Medical faculty, Lund University, opponent Tim Aitman, London

Present position: CEO, Redoxis AB, Göteborg and Pronoxis AB, Lund

20) Jens Holmberg, 041210, “Reduced ROS production triggers arthritis”Medical faculty, Lund University, opponent Cor Verweij,  Amsterdam Frije Univesity

Present position: CEO, neurodiagnostic company Lund,

21) Martina Johannesson, 050128, “Novel strategies to explore the complex genetics of autoimmune diseases”Medical faculty, Lund University, opponent Karl Broman, Baltimore University, USA

Present position: scientific coordinator, Karolinska Institutet

22) Robert Bockermann, 050523 “The role of T cells and T cell receptor polymolrphism in controlling pathways leading to arthritis”Medical faculty, Lund University, opponent Juan Lafaille, Columbia University, New York, USA

Present position: Scientist, Hansa AB, Lund

23) Estelle Bajtner, 050917,  “Role of collagen type II specific antibodies in arthritis”. Medical faculty, Lund University, opponent Marie Wahren, Karolinska Institutet, Stockholm

Present position: Scientific coordinator, Lund University

24) Stefan Carlsen, 051015, “Cartilage proteins and their antigenic properties in arthritis”, Medical faculty, Lund University, opponent Richard Williams, London, UK

Present position: Scientist, Eurodiagnostics, Malmö

25) Kutty Selva Nandakumar, 060127, “Analysis of effector pathways in arthritis”, Medical faculty, Lund University, opponent Birgitta Heyman, Uppsala University, Sweden

Present position: Associate professor, Karolinska Institutet

26) Lina Olsson, 071130, “Genetic and genomic analysis of arthritis regulating regions in human and mouse”, Medical faculty, Lund University, opponent Janna Saarela, Helsinki University, Finland

Present position: Scientist, Karolinska Instititutet

27) Emma Ahlqvist, 071201, “Identification of Arthritis Susceptibility Genes in Mice and Humans”, Medical faculty, Lund University, opponent Jonathan Flint, Oxford, England

Present position: Postdoc, Dept of Medicine-Malmö, Lund University

28) Malin Hultqvist, 071214, “The effect of reactive oxygen species (ROS) in animal models of autoimmunity”, Medical faculty, Lund University, opponent Phillip Hawkins, Cambridge University, England

Present position: research director (CRO), Redoxis AB

29) Carola Rintisch, 090213, “From disease to the gene. Identification or arthritis-regulating loci in rats”, Medical faculty, Lund University, opponent Abdelhadi Saoudi, Toulouse, France.

Present position: Postdoc, Berlin

30) Therese Lindvall, 091127, “From disease to genes in animal models of rheumatoid arthritis and multiple sclerosis”, Medical faculty, Lund University, opponent Kristina Lejon, Umeå Sweden. Present position: Scientist, Redoxis AB.

31) Angela Pizolla, 111209, “The role of macrophages in regulating inflammation by oxidative burst”, Karolinska Institutet, opponent Kristoffer Hellstrand, Göteborg University, Present position: postdoc Melbourne, Australia.

32) Michael Förster, 121027. “Genetic regulation of mouse arthritis” Karolinska Institutet, opponent Göran Andersson Uppsala University, Present position, postdoc McGill, Canada

33) Bruno Raposo, 121130. “Genetic regulation of autoantibodies in arthritis: lessons from mouse models”  opponent Dan Holmberg, Copenhagen University, Karolinska Institutet,

Present position postdoc, Karolinska Institutet

34) Ingrid Lindh, 130412, “Autoantibody regulation of collagen type II in arthritis”, Karolinska Institutet, opponent ass Prof Leendert Trouw, Leiden University, Present position; Medical Science Liaison AbbVie, Stockholm

35) Tiina Kelkka, 130426.  “Reactive oxygen species in inflammation”, University of Turku University, opponent Lars Rönnblom, Uppsala Univeristy, Present position, postdoc Helsinki

36) Jonatan Tuncel, 130601, “The Major Histocompatibility Complex and its function in Arthritis” Karolinska Institutet, opponent Jaques Neefjes, Amsterdam, Present position, postdoc Harvard

37) Sabrina Haag, 140412, “The MHC and the recognition of self and altered self in experiemtnal and rheumatoid arthritis”, opponent Prof Lars Fugger, Oxford University. Present position, postdoc Harvard

 

Main supervisor for the following lic exams: Magnus Ehinger (90), Myassa Dartell (06), Marjan Popovic (08)

 

Current PhD students (as a main supervisor):

38) Ulrika Norin (Karolinska Institutet)

39) Anthony Yau (Karolinska Institutet)

40) Cecilia Hagert (Turku University)

41) Erik Lönnbom (Karolinska Institutet)

42) Clara Marquina (Karolinska Institutet)

 

Assistant supervisor for the following PhD: 1) Per Larsson (89), 2) Inga Hansson (93), 3) Hai Tao Yang (00), 4) Ingrid Teige (04), 5) Jinan Li (04), 6) Meirav Holmdahl (05), 7) Jenny Karlsson (05), 8) Alexandra Treschow (05). 9) Patrick Merky “Posttranslational Modification of Collagen Type II Effects on Antigen Specific T-Cell Tolerance and Autoreactivity in Collagen Induced Arthritis” main supervisor Johan Bäcklund, opponent Burkhardt Becher, 110120, 10) Dorota Kolodziej “Finding genes controlling arthritis in mice- Fcg receptors and complement C5” main supervisor Kutty Selva Nandakumar opponent Sjef Verbeek, 120523, 11) Ia Khalmadze; Understanding inflammatory mechsnims in rheumatic diseases, opponent Anne Rothstein 141208

 

Current PhD students (as an assistant supervisor)

12) Katrin Klocke

13) Simon Guerad

14) Daniëlle Vaartjes

15 Dongmei Tong

16 Bibo Liang

17) Mike Auon

18) Gonzales

 

Supervised postdocs/assistants (present position in parenthesis)

Stefan Persson, 94-96 (research director Resistentia AB , Uppsala)

Liselotte Jansson 95-00 (section head, Astrazeneca Södertälje)

John A Mo 95-98 (scientist Astrazeneca Lund)

Aiping Lu 95-96 (professor Univ of Traditional Medicine Beijing)

Anna Mikulowska 96-97 (scientist, California)

Andrew Cook, 96-99 (senior lecturer, Melbourne)

Kristin Bergsteinsdottir, 96-00 (scientist company Rejkjavik)

Shohreh Issazadeh-Navikas 98-05 (professor Copenhagen University)

Åsa Andersson 98-05 (associated prof Copenhagen University)

Ragnar Mattsson 98-99 (professor Lund University)

Jesper Tordsson (01)

Anna Karin Lindqvist, 01-04 (CRO Cartela AB, Lund)

Hisakata Yamada, 01-03 (senior lecturer, Fukukou University)

Shemin Lu, 02-04 (Professor and Head of Immunology, Xian University)

Balik Dzambazhov 02-04, 05-07 (Professor, dean, Plovdic University)

Kang Feng 03-04 (assistant professor, New York)

Ming Zhao, 03-04 (professor, China SouthWestern University)

Lena Wester-Rosenlöf, 04-06 (scientist, Rostock University)

Kyra Gelderman, 04-06 (scientist Amsterdam Univ)

Ivanka Teneva 05-07 (ass prof, Plovdic University)

Johan Bäcklund 05-08 (ass professor, Karolinska Institute)

Duoija Cao 05-09

Kristin Bauer/Hagenow 06-09 (scientific coordinator, Berlin)

Kutty Selva Nandakumar 06-08 (ass professor, Karolinska Institute)

Franziska Lange 08-09, scientist, Leipzig University

Outi Sareila 08-

Kajsa Wing 08-11 (ass prof, Karolinska Institutet)

Huseyin Uysal 08-11 (ass Professor, Turkey)

Liselotte Bäckdahl 09-

Markus Hoffmann 10-11 (Group leaqder, erlangen)

Christoph Kessel 09-11 (Group leader)

Frida Laulund 10-11

Ida Andersson 11-13

Changron Ge 11-

Lina Olsson 11-

Martina Johannesson 11-14 (coordinator, BeTheCure project)

Susann Winter 12-

Vilma Urbonaviciute 12-

Amit Saxena 12-

Florian Förster 12-15

Min Yang 12-

Jianghong Zhong 12-

 

I. Opponent

1) Åsa Andersson 93, “B cell repertoire development in normal pysiology and autoimmune disease”, Medical Faculty, Umeå University 1993

2) Anna Ridderstad 94, Science Faculty, Stockholm University

3) Xue-Feng Bai 980116, Modulation of experimental T cell autoimmunity in the nervous system with emphasis on nasal tolerance, Karolinska Institute, Stockholm 1998

4) Johnny Lorentzen 980321, “Pathogenesis of arthritis in rats. Genetic factors and inducing molecules”, Karolinska Institute, Stockholm 1998

5) Kristian Bartnes 980402, “Major histocompatibility complex (MHC) class II-associated presentation of immunoglobulin (Ig)-derived peptides and T/B lymphocyte interactions across T-cell antigen receptor/Ig peptide/MHC class II bridges”, Medical Faculty, Tromsö University 1998

6) Oyvind Molberg 981127, “T cells of the human small intestinal mucosa. Studies of HLA restriction and antigen-specificity with particular reference to coeliac disease.”, Medical Faculty, Oslo University 1998.

7) Mitchell Krogsgaard 990315, “Generation of recombinant antibodies specific for MHC/peptide complexes of relevance for the pathogenesis of multiple sclerosis” The Royal Danish School of Pharmacy, Copenhagen University 1999.

8) Teis Jensen 000515, “T cell recognition of glycopeptides – a cellular and molecular view” Sundhetsvidenskaplig fakultet, Copenhagen University 1999.

9) Olof Hultgren 000525, “Cytokines in Staphylococcus aureus arthritis. For better for worse.” Medical Faculty, Göteborg University 2000

10) Ling-Yun Xu 001124, “Mechanisms and modulation of experimental allergic encephalomyelitis as basis for treatment of multiple sclerosis.”  Karolinska Institute 2000

11) Molly Vernersson 021007, “The rise and fall of IgE”  Uppsala University, Science Faculty 2002

12) Helle Jacobsen 040422, “A functional and structural basis for TCR crossreactivity in multiple sclerosis”, Copenhagen University, Clinical Immunology 2004

13) Max Benner 060524, Feinstein College of Medicine, Long Island, New York

14) Ulrika Islander, 070321 Göteborg University Medical Faculty, 2007

15) Sreeram V. Ramagopalan, 081118 Oxford University Medical Faculty, England, 2008

16) Sandra Karlsson, 081219 Göteborg University, Science Faculty, 2008

17) Line Mari Flornes, 100813 Oslo Univeristy, Medical faculty, 2010

18) Anu Kemppinen, 111007 Helsinki University, 2011

19) Mia Olsson, 121213 Uppsala University, 2012

 

J. Previous research accomplishments

The research achievements so far obtained are mainly:

• The identification of the major gene associated with CIA (Aq) and its human functional homologue (DRB1*0401) using humanized mice

• The identification of a glycopeptide within the type II collagen molecule as binding DR4 and Aq and being a major T cell recognition peptide in CIA and RA

• The identification of the major gene regions associated with disease in mouse and rat models for MS and RA

• The cloning of the Ncf1 gene responsible for a major locus associated with arthritis (Pia4) and thereby discovery of a new pathway for how oxidative radicals regulate the adaptive immune system

• Demonstration of pathogenicity and molecular interaction of antibodies specifc for citrullinated proteins, of critical importance in rheumatoid arthritis

 

K. Current participation in international cooperations and national networks:

• EU; FP7 integrated project (EURATRANS) 10-15, partner

• EU; IMI project (BTCure) 11-16, partner, leading standardization of animal models for RA in Europe

• EU; FP7 integrated project (Neurinox) 12-17, partner

• EU; Marie Curie training center (Osteoimmune) 12-17, partner

2008-CERIC Linné Center supported by the Swedish Research Council (Vetenskapsrådet)

2008-2013-COMBINE: an joined project and funded by six Swedish Research organizations, Vinnova, Vårdalstiftelsen, Reumatikerförbundet, Invest in Sweden Agency, KK-stiftelsen, Stiftelsen för strategisk forskning

2011-KI selected ThemeCenter for Inflammatory Diseases

2012-Center for Autoimmune Diseases, supported by Wallenbergs Stiftelse

2015-Biomarkers for detection of Joint inflammation, supported by SSF

 

L. Description of the current research group

A research environment (see our homepage http://www.inflam.mbb.ki.se) has been created with the goal to be world-leading in the field of complex genetics and immunology of chonic inflammatory diseases using animal models. Our main emphasis is on autoimmune diseases, using models for arthritis as a prototype disease. Identified genes are investigated through their molecular pathogenic pathway and therapy is developed with the aim to transfer the knowledge into clinical use. The laboratory and the connected animalhouse are organized for performing the outlined work. Today the laboratory consists of 4 principal investigators (including my self), 10 PhD students and 10 postdocs as well as technical and administrative staff. In this environment many PhD students and postdocs have completed their thesis and they are now in career positions in academia or pharma industry.

 

M. Summary of research program

We search for basic biological knowledge explaining the development of chronic inflammatory disorders (CID), such as rheumatoid arthritis, multiple sclerosis, psoriasis and atherosclerosis. The goal is to identify prognostic markers and to establish new therapies for chronic inflammatory diseases. We have the following more specific goals:

1) To identify the most important genes that control pathogenic inflammation using an experimental animal platform.

2) To translate the identifications of genes and pathways in the animal models to human CID’s

3) To understand the role of MHC class II genes in explaining the immune specificity of autoimmune disease and to develop a new type of vaccine for treatment of rheumatoid arthritis

4) To understand the Ncf1(NOX2) controlled downstream oxidation pathway associated with severe inflammation and to develop a new type of anti-inflammatory treatment based on oxidants.

 

N. Publication summary

530 publications (440 peer reviewed original articles, 53 peer reviewed overviews, 25 books/book chapters, 12 patents, 1 thesis, 1 popular press) + approximately 200 abstracts/conference proceedings

Thomson: 16621 citations, h-index 69. Google Scholar: 21873 citations, h-index 80

Research

Research overview

 

Human diseases: rheumatoid arthritis (RA), multiple sclerosis (MS)

There are a number of diseases, called "autoimmune", in which specific tissues are attacked by an immune mediated destructive and chronic inflammation without any evidence for infection or allergy. There are several of our most important diseases in this group such as rheumatoid arthritis (RA), multiple sclerosis (MS), type I diabetes, Sjögren syndrome (SS) and systemic lupus erythematosus (SLE). In spite of enormous research efforts resulting in a large number of publications we know in fact very little about the cause of the diseases. We do not know if they are autoimmune, we do not know which genes predispose for disease or which environmental factors that triggers them and more importantly, there are no current effective treatments that can reverse the disease course. We strongly believe that we need to take one step back to take two steps forward. We need to understand the pathogenic events that lead to the chronic development of tissue destruction in these diseases. And this is best done using animal models in which such basic questions can be addressed. 

Characteristics of "autoimmune" inflammatory conditions such as RA and MS:

> They are syndromes caused by many different pathways;
> They are inflammatory states affecting primarily specific tissues with limited exposure to the immune system;
> They are chronic;
> They are dependent on a clear genetic influence (10-50% concordance in MZ studies), and the genetic influence is to a significant degree associated with genes in the major histocompatibility complex (MHC).

Genetics of RA and MS

The disease manifestations in RA and MS are very complex and it is easy to document activity of most pathways, cytokines, receptors or cells that one might be interested. This does not however directly address the pathogenic disease mechanisms. There must be a number of crucial events, determine by genes and environmental factors that promote the development of an otherwise normal process into pathology. In fact, there are high expectations from scientists and the public that we should be able to identify such genes through the recent advancement of genome research and also expectations from politicians that we could understand the diseases through epidemiological scans of environmental factors. The problem is that these diseases are quite complex, not only in their pathogenesis, but also in their genetic control and the influence by environmental factors.

Obstacles in defining genes causing a complex disease such as RA and MS:

   * Phenotypic heterogeneity. There are many different clinical variants of the disease that needs to be distinguished;
   * Genetic heterogeneity. The same disease could be caused by different sets of genes in different individuals;
   * Polygenicity – controlled by many genes. Many of these penetrate only upon interaction;
   * Complexity – influence by environmental and stochastic factors.

However, we think there is a way out. This is to combine genetics with animal models in which specific pathogenic pathways can be studied. Not only genetics has been better but also animal models. It is today possible to more precisely study specific pathways leading to autoimmune disease in animal models. These pathways are evolutionary conserved and the fact that diseases develop, or can be induced, in animals leads to disease that mimic the human counterpart shows that such pathways can result in similar type of disease. Animals offer new possibilities since they are inbred, they can be bred systematically with short generation times and they can be manipulated genetically and also with induction of disease.

Animal models

In the laboratory we are trying to improve the animal models for different autoimmune disease. This will lead to more efficient progress in research to understand the human disease and will thereby also reduce the animal suffering. We have made significant contribution to this and introduced more appropriate models and ways to induce them for both RA and MS.
It is also important to have many different models for these disease since both RA and MS is most liklely consisting of many different disease; each of which may be represented by different animal models.

Animal models for inflammatory diseases in the MIR laboratory:

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Disease	Model
Rheumatoid arthritis	– Collagen induced arthritis (CIA) in mice and rats; – Pristane induced arthritis (PIA) in rats; – Cartilage oligomeric matrix protein induced arthritis (COMPIA); – Autologous type XI collagen induced arthritis (CXIIA); – Anti-CII antibody induced arthritis (CAIA).
Multiple sclerosis	– Chronic relapsing experimental allergic encephalomyelitis (EAE) in mice and rats.
Spondyloarthropathis	– Stress induced enthesiopathy (SIA).
Sjögren´s syndrome	– Spontaneously occuring in selected mouse strains.
Relapsing polychondritis	– Matriline-1 induced relapsing polychondritis (MIRP).
Systemic lupus erythematosus	– Spontaneously occuring in selected mouse strains.
Type I diabetes	– Spontaneously occuring in selected mouse strains.

---

 Our main goals are:

1) To identify the most important genes that control relevant animal models for rheumatoid arthritis and multiple sclerosis. In particular we aim to understand the genes determining the pathogenic events transforming the disease into chronicity.

2) To understand the role of MHC class II genes in explaining the immune specificity of autoimmune disease.

3) To use the animal models not only for understanding the basic mechanism of autoimmune disease but also as models for developing new diagnostic, preventive and therapeutic strategies for autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.

Genetic studies in animal models

We search for genes controlling disease and specific disease pathways by analysing gene segregating crosses between resistant and susceptible strains. By genotyping the offsprings we try to identify the most important gene regions associated with disease. Subsequently, we can isolate these gene regions in so called congenic strains. The congenic strains can be used to understand the biological role of the genes and also identify the responsible gene or genes in these regions.
We have so far identified genetically inbred strains that differ in susceptibility to many of the animal models for RA and mS and other disease and have identified the genetic regions that harbour the polymorphic genes of interest. We believe that these genes will be of critical importance to understand the critical pathogenic events in the disease. It should however be emphasised that it has not yet been possible to identify such a gene in any autoimmune complex disorder, possibly except MHC class II as discussed below. The animal models do, however, provide excellent possibilities for such studies and it is a question of time when these genes will bed unravelled. It will however be quite complicated to understand how they interact and their exact role in the pathogenesis. Many projects in our laboratory aim to identify these genes and understand how they work, For these studies we use a series of congenic strains in both mice and rats controlling different pathways leading to disease. We are trying to isolate genes by positional cloning and comparative mapping technology and the diferent pathways studied with identification of differentially expressed genes using microarray technology.

 

The major histocompatibility complex region: the role of T and B cells

Most autoimmune diseases are associated with the MHC region, in RA and MS with the class II region of MHC. However, it has not been possible to identify the responsible genes and its not clear how thye affect the disease process. Very challenging data has been accumulated in RA in which it has been shown that most DR alleles that are associated with disease share a particular sequence in the peptide binding region of the class II molecule. This is a strong argument for a role of the class II gene and for a role of immune specificity in the disease.

Also in most animal models for RA it has been possible to identify the MHC region to be important. In one of these models, in collagen induced arthritis in the mouse, we were able to produce conclusive evidence of the MHC class II Abq gene to be important. We also know considerable details on recognition structures but do still not know exactly how it is operating for disease development. We have also shown that this gene product is strikingly similar to the DR molecule postulated to play a role in RA and shown that the expression of the human DR4 gene in the mouse in fact also predispose for the same type of collagen induced arthritis. We have obtained similar findings using models for MS. Thus, it is possible to identify genes in the animal model and it is possible to humanise the mice and it will most likely be possible in the future to understand its function. Of particular relevance will be to understand its function together with other genes of importance for the disease.

The MHC class II molecules are cell membrane peptide receptors – the peptides are the antigen recognized by T cells. This interaction is a critical step in antigen-specific T cell activation and is possibly a critical step also in the development of autoimmune diseases. We have identified the peptides bound to the Aq molecule, the CII256-270 peptide derived from the type II collagen molecule and we know that the major recognition structure is a carbohydrate bound to lysine at position 264. T cell recognition of this structure is bottleneck for development of CIA. We also know that T cells normally recognize this structure in vivo. After interaction they can be deleted, or tolerized, thus normally preventing development of arthritis. However, when the mice are immunized with CII these T cells seem to be possible to activate to a state when they can start a process leading to arthritis. Many projects in the lab aim understand how this occurs and in these projects we use mice that are transgenic or mutated in T cell receptors, type II collagen and MHC.

One important step towards arthritis is the activation of B cells. B cells can be activated to produce antibodies to CII but requires help from CII reactive T cells. These B cells produce antibodies that can directly cause arthritis through binding to the cartilage surface and initiating complement and Fc-receptor dependent inflammatory cascades. There are projects in the laboratory aiming to understand which structures are recognized by these arthritogenic antibodies, how B-cells are regulated, if B cell can present CII to T ell through their own class II molecules and how the antibody attack on cartilage is mediated and controlled. For these studies we are using mice genetically mutated in the specific epitopes on CII and mice with various defects in B cells and MHC molecules. Similar projects on MHC, the role of T and B cells and their activation are also ongoing in models for MS.